Thyroglobulin proteolysis and thyroid hormone release occur within phagolysosomes formed by the fusion of colloid droplets and lysosomes. These subcellular organelles can be sedimented in an 800-15,000 x g (P15) fraction of thyroid. Previous studies have demonstrated the presence of thyroglobulin and smaller iodoprotein intermediates within these organelles and a relative increase in intermediates after TSH stimulation in vivo. Since some thyroglobulin is known to be present in the circulation in normal man and animals, it is possible that proteolytic digestion is not always complete and that some of the smaller thyroglobulin intermediates may also be released to the circulation. Studies are underway to characterize and quantitate thyroglobulin and its iodoprotein intermediates in human serum in different thyroid states. Examination for antibodies to thyroglobulin and its intermediates by radioimmunological assay will also be made in the hope of determining a possible defect in thyroglobulin proteolysis and the immunological pathogenesis of autoimmune thyroid disease. Correlation of lysosomal enzyme activities with the electron microscopic appearance of lysosomal activity will be made in animals and also in human glands from normal and pathological thyroid states.